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Cocaine and the Long-Term Risk of Cardiovascular Disease in Women

  • U. Vivian Ukah
    Affiliations
    Department of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, Quebec, Canada

    Institut national de santé publique du Québec, Montreal, Quebec, Canada
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  • Brian J. Potter
    Affiliations
    Division of Cardiology, Department of Medicine, University of Montreal Hospital Centre, Quebec, Canada

    University of Montreal Hospital Research Centre, Quebec, Canada
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  • Gilles Paradis
    Affiliations
    Department of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, Quebec, Canada

    Institut national de santé publique du Québec, Montreal, Quebec, Canada
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  • Nancy Low
    Affiliations
    Department of Psychiatry, McGill University, Montreal, Quebec, Canada
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  • Aimina Ayoub
    Affiliations
    Institut national de santé publique du Québec, Montreal, Quebec, Canada

    University of Montreal Hospital Research Centre, Quebec, Canada
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  • Nathalie Auger
    Correspondence
    Requests for reprints should be addressed to Nathalie Auger, MD, MSc, Institut national de santé publique du Québec, 190 Cremazie Blvd E, Montreal, Quebec H2P 1E2, Canada
    Affiliations
    Department of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, Quebec, Canada

    Institut national de santé publique du Québec, Montreal, Quebec, Canada

    University of Montreal Hospital Research Centre, Quebec, Canada

    Department of Social and Preventive Medicine, School of Public Health, University of Montreal, Quebec, Canada
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      Abstract

      Background

      Cocaine is associated with acute cardiovascular complications, but the long-term cardiovascular risks of cocaine use are poorly understood. We examined the association between cocaine use disorders and long-term cardiovascular morbidity in women.

      Methods

      We analyzed a longitudinal cohort of 1,296,463 women in Quebec, Canada between 1989 and 2020. The exposure included cocaine use disorders prior to or during pregnancy. The outcome was cardiovascular hospitalization up to 31 years later. We used adjusted Cox regression models to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the association of cocaine use disorders with cardiovascular hospitalization.

      Results

      The cohort included 2954 women with cocaine use disorders. Compared with women without an identified cocaine disorder, women with cocaine use disorders had 1.55 times greater risk of future cardiovascular hospitalization during 3 decades of follow-up (95% CI, 1.37-1.75). Cocaine use disorders were strongly associated with inflammatory heart disease (HR 4.82; 95% CI, 2.97-7.83), cardiac arrest (HR 2.93; 95% CI, 1.46-5.88), valve disease (HR 3.09; 95% CI, 2.11-4.51), and arterial embolism (HR 2.22; 95% CI, 1.19-4.14). The association between cocaine use disorder and cardiovascular hospitalization was most marked after 5 to 10 years of follow-up (HR 2.15; 95% CI, 1.70-2.72).

      Conclusions

      Women with cocaine use disorders have a high risk of cardiovascular hospitalization up to 3 decades later. Substance use reduction and cardiovascular risk surveillance may help reduce the burden of cardiovascular disease in women with cocaine use disorders.

      Keywords

      Clinical Significance
      • Cocaine use was associated with risk of cardiovascular disease up to 30 years later.
      • Women who used cocaine were at risk of a wide range of cardiovascular problems.
      • Risks were more pronounced 5 to 10 years after the start of follow-up.

      Introduction

      Cardiovascular disease is a leading cause of death in women,
      • Garcia M
      • Mulvagh SL
      • Merz CN
      • Buring JE
      • Manson JE
      Cardiovascular disease in women: clinical perspectives.
      yet little attention is paid to illicit substances that can adversely affect the cardiovascular system.
      • Auger N
      • Paradis G
      • Low N
      • Ayoub A
      • He S
      • Potter BJ
      Cannabis use disorder and the future risk of cardiovascular disease in parous women: a longitudinal cohort study.
      • Kevil CG
      • Goeders NE
      • Woolard MD
      • et al.
      Methamphetamine use and cardiovascular disease.
      • Talarico GP
      • Crosta ML
      • Giannico MB
      • Summaria F
      • Calò L
      • Patrizi R
      Cocaine and coronary artery diseases: a systematic review of the literature.
      Mortality due to substance use is increasing in women, including deaths from stimulants such as cocaine.
      • Kariisa M
      • Scholl L
      • Wilson N
      • Seth P
      • Hoots B
      Drug overdose deaths involving cocaine and psychostimulants with abuse potential - United States, 2003-2017.
      Cocaine is derived from Erythroxylum coca (coca bush) and is one of the most frequently used illicit substances in North America. Reports suggest that about 1% of adolescent girls and young women use cocaine.

      Canadian Centre on Substance Use and Addiction. Canadian Drug Summary: Cocaine. 2019. Available at:https://www.ccsa.ca/sites/default/files/2019-04/CCSA-Canadian-Drug-Summary-Cocaine-2019-en.pdf. Accessed May 21, 2021.

      • Kann L
      • McManus T
      • Harris WA
      • et al.
      Youth risk behavior surveillance - United States, 2017.
      • Wong S
      • Ordean A
      • Kahan M
      • et al.
      Substance use in pregnancy.
      Cocaine is extremely addictive and may lead to cocaine use disorders that have a significant impact on women.

      Canadian Centre on Substance Use and Addiction. Canadian Drug Summary: Cocaine. 2019. Available at:https://www.ccsa.ca/sites/default/files/2019-04/CCSA-Canadian-Drug-Summary-Cocaine-2019-en.pdf. Accessed May 21, 2021.

      ,
      • Chen DH
      • Kolossváry M
      • Chen S
      • Lai H
      • Yeh HC
      • Lai S
      Long-term cocaine use is associated with increased coronary plaque burden – a pilot study.
      Cocaine contributes considerably to substance-related mortality in young women,
      • Kariisa M
      • Scholl L
      • Wilson N
      • Seth P
      • Hoots B
      Drug overdose deaths involving cocaine and psychostimulants with abuse potential - United States, 2003-2017.
      but the influence of cocaine use disorders on risk of cardiovascular disease in women of reproductive age has not been studied.
      The acute effects of cocaine on the cardiovascular system are well known. Short-term use of cocaine is associated with greater atherosclerotic plaque volume, increased incidence of myocardial infarction, and sudden cardiovascular death.
      • Talarico GP
      • Crosta ML
      • Giannico MB
      • Summaria F
      • Calò L
      • Patrizi R
      Cocaine and coronary artery diseases: a systematic review of the literature.
      ,
      • Chen DH
      • Kolossváry M
      • Chen S
      • Lai H
      • Yeh HC
      • Lai S
      Long-term cocaine use is associated with increased coronary plaque burden – a pilot study.
      However, the medium and long-term cardiovascular risks of cocaine use are less understood, particularly among women. In an analysis of approximately 2000 patients, women who used cocaine on a regular basis were twice as likely as non-users to suffer from hypertension up to 5 years later, while there was no association in men.
      • Braun BL
      • Murray DM
      • Sidney S
      Lifetime cocaine use and cardiovascular characteristics among young adults: the CARDIA study.
      Women who use cocaine during pregnancy have greater odds of myocardial infarction and cardiac arrest during pregnancy and delivery.
      • Salihu HM
      • Salemi JL
      • Aggarwal A
      • et al.
      Opioid drug use and acute cardiac events among pregnant women in the United States.
      A study of 321 women suggested that cocaine use during pregnancy was associated with a greater risk of heart failure 10 years later.
      • Minnes S
      • Min MO
      • Singer LT
      • Edguer M
      • Wu M
      • Thi P
      Cocaine use during pregnancy and health outcome after 10 years.
      Cocaine use during pregnancy is associated with a two- to threefold greater risk of adverse birth outcomes, including preterm birth, low birth weight, and placental disorders.
      • Dos Santos JF
      • de Melo Bastos Cavalcante C
      • Barbosa FT
      • et al.
      Maternal, fetal and neonatal consequences associated with the use of crack cocaine during the gestational period: a systematic review and meta-analysis.
      ,
      • Mbah AK
      • Alio AP
      • Fombo DW
      • Bruder K
      • Dagne G
      • Salihu HM
      Association between cocaine abuse in pregnancy and placenta-associated syndromes using propensity score matching approach.
      These pregnancy complications are also associated with an increased risk of cardiovascular disease.
      • Parikh NI
      • Gonzalez JM
      • Anderson CAM
      • et al.
      Adverse pregnancy outcomes and cardiovascular disease risk: unique opportunities for cardiovascular disease prevention in women: a scientific statement from the American Heart Association.
      Characterizing the link between cocaine use disorders and future cardiovascular events is needed to tailor prevention and surveillance efforts in women. We therefore examined the relationship between cocaine use disorders and risk of cardiovascular hospitalization over the course of 3 decades in a large population of parous women.

      Materials and Methods

      Study Design and Population

      We designed a longitudinal cohort study of 1,296,463 parous women in Quebec, Canada between 1989 and 2019. We extracted the women from the Maintenance and Use of Data for the Study of Hospital Clientele registry.
      Ministry of Health and Social Services
      Med-Echo System Normative Framework - Maintenance and Use of Data for the Study of Hospital Clientele.
      The dataset contains discharge abstracts for all hospitalizations in Quebec since April 1989, including 99% of deliveries. The cohort is representative of parous women in the province and is extensively validated to ensure accuracy of data.
      Ministry of Health and Social Services
      Med-Echo System Normative Framework - Maintenance and Use of Data for the Study of Hospital Clientele.
      Using health insurance numbers, we followed women from their last pregnancy to the end of the study on March 31, 2020, to identify cardiovascular hospitalizations. Follow-up extended from the last pregnancy up to 31 years later. We excluded women with a history of cardiovascular disease prior to their last pregnancy to focus on the long-term implications of cocaine use among women with no known short-term cardiovascular complications. We also excluded women who could not be followed over time due to missing health insurance numbers.

      Cocaine Use Disorders

      The main exposure was a cocaine use disorder prior to or during pregnancy, including cocaine abuse, dependence, overdose, or poisoning. We identified women with cocaine use disorders using data from the delivery hospitalization. Hospital charts at delivery contain information on a woman's entire obstetric history, including cocaine use in any pregnancy that was self-reported or detected through toxicology tests during prenatal care. We additionally identified women who were hospitalized with cocaine use disorders prior to pregnancy.
      We further determined whether cocaine was used alone or combined with other substances (cocaine with other substance use disorder, cocaine use disorder alone, other substance use disorder alone, no substance use disorder). As data suggest that cannabis may increase the risk of cardiovascular disease,
      • Auger N
      • Paradis G
      • Low N
      • Ayoub A
      • He S
      • Potter BJ
      Cannabis use disorder and the future risk of cardiovascular disease in parous women: a longitudinal cohort study.
      we also examined the use of cocaine combined with cannabis. We identified the timing of cocaine use (during pregnancy, prior to pregnancy, no cocaine use). We used diagnostic codes from the 9th and 10th revisions of the International Classification of Diseases to identify cocaine and other substance use disorders.
      • Auger N
      • Paradis G
      • Low N
      • Ayoub A
      • He S
      • Potter BJ
      Cannabis use disorder and the future risk of cardiovascular disease in parous women: a longitudinal cohort study.
      Duration of substance use was not known.

      Cardiovascular Outcomes

      The main outcome consisted of hospitalization for cardiovascular disease between the start and end of follow-up. We used International Classification of Diseases codes to identify admissions for cardiovascular disease, including heart failure, myocardial infarction, other ischemic heart disease, angina, cardiac arrest, inflammatory heart disease (pericarditis, endocarditis, myocarditis), conduction disorder, valve disease, cardiomyopathy, pulmonary heart disease (pulmonary embolism, other pulmonary vascular disease), cerebrovascular disease (ischemic stroke, hemorrhagic stroke, other cerebrovascular disease), hypertension, atherosclerosis, aortic aneurysm or dissection, other vessel aneurysm, and arterial embolism.
      • Auger N
      • Paradis G
      • Low N
      • Ayoub A
      • He S
      • Potter BJ
      Cannabis use disorder and the future risk of cardiovascular disease in parous women: a longitudinal cohort study.
      We additionally used procedure codes from the Canadian Classification of Diagnostic, Therapeutic, and Surgical Procedures and the Canadian Classification of Health Interventions to capture cardiovascular interventions, including heart procedures (coronary angioplasty, coronary artery bypass graft, valve surgery, pacemaker insertion, cardiac transplant, cardiopulmonary resuscitation, open heart resuscitation), vessel procedures (aorta surgery, intracranial surgery), and admission to a coronary care unit.
      • Auger N
      • Paradis G
      • Low N
      • Ayoub A
      • He S
      • Potter BJ
      Cannabis use disorder and the future risk of cardiovascular disease in parous women: a longitudinal cohort study.

      Covariates

      We considered potential confounders, including age (<25, 25-34, ≥35 years); parity (1, 2, ≥3 deliveries); history of mental illness, defined as schizophrenia, depression, bipolar, anxiety, stress, personality disorders, and suicide attempt; other substance use disorders (alcohol, opioids, cannabis, stimulants, hallucinogens, sedatives, hypnotics, and volatile solvents), tobacco use disorders; and comorbidity defined as preexisting or gestational diabetes, obesity, and dyslipidemia.
      • Auger N
      • Paradis G
      • Low N
      • Ayoub A
      • He S
      • Potter BJ
      Cannabis use disorder and the future risk of cardiovascular disease in parous women: a longitudinal cohort study.
      We accounted for socioeconomic deprivation defined as the most deprived fifth of the population, based on a neighborhood-level composite measure of income, education, and employment.
      • Auger N
      • Paradis G
      • Low N
      • Ayoub A
      • He S
      • Potter BJ
      Cannabis use disorder and the future risk of cardiovascular disease in parous women: a longitudinal cohort study.
      Finally, we included rural residence and time period (1989-1998, 1999-2008, 2009-2019) as covariates. We measured all covariates at the last pregnancy when follow-up started.

      Data Analysis

      We followed the cohort of women over time until their first cardiovascular hospitalization, death, or the study end. We calculated the incidence of cardiovascular hospitalization per 10,000 person-years in women with and without a history of cocaine use disorder. We used Cox proportional hazards regression models adjusted for age, parity, mental illness, other substance use disorders, tobacco use, comorbidity, socioeconomic deprivation, place of residence, and time period to measure the association of cocaine use disorders with the subsequent risk of cardiovascular hospitalization. Upon verification of the proportional hazards assumption through survival curves, we used the Cox models to estimate hazard ratios (HR) and 95% confidence intervals (CI), comparing cocaine use disorder relative to no cocaine use disorder. The time scale consisted of the number of days since the start of follow-up. We accounted for death as a competing event,
      • So Y
      • Lin G
      • Johnston G
      Using the PHREG procedure to analyze competing-risks data.
      and censored women who did not have a cardiovascular event prior to the end of the study.
      In secondary analyses, we assessed how comorbid substance use and the timing of cocaine exposure influenced the association of cocaine use disorders with cardiovascular hospitalization. We also determined how cocaine use disorders were associated with different cardiovascular diseases and interventions. Finally, we assessed whether the risk of cardiovascular disease varied over time by examining associations at different follow-up intervals (<5, 5-9, 10-14, and ≥15 years).
      In sensitivity analyses, we analyzed cocaine use disorders as a time-varying exposure, starting follow-up at the first delivery rather than the last. We also tested models that were not adjusted for other substance use disorders and models that were restricted to primiparous women aged 35 years or more. All analyses were carried out in SAS version 9.4 (SAS Institute Inc., Cary, NC). We use de-identified data and therefore obtained an ethics waiver from the institutional review board of our research institution.

      Results

      In this longitudinal cohort of 1,296,463 parous women, 2954 women (0.2%) had a cocaine use disorder prior to or during pregnancy. A large proportion of the women in the cohort were between the ages of 25 and 34 years (67.0%) and nulliparous (42.8%). Approximately 18% lived in rural areas and 3.6% had a history of mental illness. Only 2.8% had a tobacco use disorder and 0.8% other substance use disorders.
      Among women with cocaine use disorders, 42.6% used cocaine during pregnancy (Table 1). Women with cocaine use disorders during pregnancy were more likely to be under 25 years of age, have greater parity, and be socioeconomically deprived, compared with no cocaine use disorder or disorders prior to pregnancy. Women with cocaine use disorders prior to pregnancy were, however, more likely to have a history of mental illness and other substance use disorders and live in rural areas, compared with no cocaine use disorder or cocaine use during pregnancy.
      Table 1Baseline Characteristics of Women with and Without Cocaine Use Disorders
      No. Women (%)
      Cocaine Use Disorder During Pregnancy
      Women with cocaine use disorders documented during pregnancy, whether or not they used cocaine prior to pregnancy.
      Cocaine Use Disorder Prior to Pregnancy
      Women with cocaine use disorders documented only prior to pregnancy.
      No Cocaine Use Disorder
      Age, years
       <25235 (18.7)271 (16.0)152,774 (11.8)
       25-34752 (59.8)1052 (62.0)867,129 (67.0)
       ≥35270 (21.5)374 (22.0)273,606 (21.2)
      Parity
       1380 (30.2)665 (39.2)554,398 (42.9)
       2333 (26.5)553 (32.6)532,426 (41.2)
       ≥3544 (43.3)479 (28.2)206,685 (16.0)
      Mental illness
      Schizophrenia, depression, bipolar, anxiety, stress, personality disorders, and suicide attempt.
      354 (28.2)1255 (74.0)45,324 (3.5)
      Other substance use disorder
      Alcohol, opioids, cannabis, stimulants, hallucinogens, sedatives, hypnotics, and volatile solvents.
      786 (62.5)1336 (78.7)13,477 (1.0)
      Tobacco use372 (29.6)473 (27.9)35,086 (2.7)
      Comorbidity
      Preexisting or gestational diabetes, obesity, and dyslipidemia.
      204 (16.2)312 (18.4)145,316 (11.2)
      Socioeconomic deprivation488 (38.8)553 (32.6)246,980 (19.1)
      Rural residence252 (20.0)434 (25.6)235,600 (18.2)
      Time period
       1989-1998335 (26.7)327 (19.3)429,496 (33.2)
       1999-2008388 (30.9)525 (30.9)339,012 (26.2)
       2009-2019534 (42.5)845 (49.8)525,001 (40.6)
      Total1257 (100.0)1697 (100.0)1,293,509 (100.0)
      low asterisk Women with cocaine use disorders documented during pregnancy, whether or not they used cocaine prior to pregnancy.
      Women with cocaine use disorders documented only prior to pregnancy.
      Schizophrenia, depression, bipolar, anxiety, stress, personality disorders, and suicide attempt.
      § Alcohol, opioids, cannabis, stimulants, hallucinogens, sedatives, hypnotics, and volatile solvents.
      Preexisting or gestational diabetes, obesity, and dyslipidemia.
      Mean and median length of follow-up of patients in the cohort were 15.0 and 14.2 years, respectively. A total of 64,653 women were hospitalized for a cardiovascular condition during 18,958,171 person-years of follow-up, including 345 women (0.5%) with cocaine use disorders (Supplementary Table, available online). Cardiovascular hospitalization rates were higher in women with cocaine use disorders (97.6 per 10,000 person-years; 95% CI, 87.8-108.4) than no cocaine use disorder (34.0 per 10,000 person-years; 95% CI, 33.7-34.2).
      After adjusting for covariates such as age and other substance use, cocaine use disorders were associated with an increased risk of cardiovascular hospitalization during follow-up (Table 2). Compared with no cocaine disorder, having a cocaine use disorder was associated with 1.55 times the risk of cardiovascular hospitalization (95% CI, 1.37-1.75). Relative to no substance use disorder of any type, women who used cocaine alone or with other substances both had more than 2 times the risk of cardiovascular hospitalization, whereas the association was slightly less pronounced for women who used other substances without cocaine. Compared with no cocaine or cannabis use disorder, women who used cocaine alone or with cannabis also had elevated risks of cardiovascular hospitalization. Compared with no cocaine disorder, cocaine use disorders during and prior to pregnancy were both associated with the risk of cardiovascular hospitalization.
      Table 2Association Between Cocaine Use Disorder and Cardiovascular Hospitalization
      No. WomenNo. Cardiovascular HospitalizationsIncidence per 10,000 Person-Years (95% Confidence Interval)Hazard Ratio

      (95% Confidence Interval)
      UnadjustedAdjusted
      Adjusted for age, parity, mental illness, tobacco use, comorbidity, socioeconomic deprivation, place of residence, and time period.
      Cocaine use disorder
       Yes295434597.6 (87.8-108.4)3.34 (3.00-3.73)1.55 (1.37-1.75)
      Additionally adjusted for other substance use disorders.
       No1,293,50964,30834.0 (33.7-34.2)ReferentReferent
      Comorbid substance use
       Cocaine with other substance use disorder2122235102.3 (90.1-116.3)3.73 (3.27-4.25)2.11 (1.84-2.42)
       Cocaine use alone83211088.7 (73.6-106.9)2.80 (2.31-3.40)2.15 (1.77-2.61)
       Other substance use alone13,47785966.2 (61.9-70.8)2.55 (2.38-2.73)1.59 (1.48-1.72)
       No substance use1,280,03263,44933.8 (33.5-34.0)ReferentReferent
      Comorbid cannabis use
       Cocaine with cannabis use disorder7766289.2 (69.6-114.4)3.67 (2.85-4.73)1.44 (1.11-1.86)
      Additionally adjusted for other substance use disorders.
       Cocaine use alone217828399.6 (88.7-111.9)3.29 (2.91-3.71)1.62 (1.42-1.85)
      Additionally adjusted for other substance use disorders.
       Cannabis use alone347211349.7 (41.3-59.7)2.51 (2.09-3.02)1.19 (0.98-1.43)
      Additionally adjusted for other substance use disorders.
       No substance use1,290,03764,19534.0 (33.7-34.2)ReferentReferent
      Timing of cocaine use
       During pregnancy125714790.9 (77.3-106.8)2.92 (2.47-3.46)1.73 (1.46-2.06)
      Additionally adjusted for other substance use disorders.
       Prior to pregnancy1697198103.4 (89.9-118.8)3.72 (3.22-4.29)1.43 (1.23-1.68)
      Additionally adjusted for other substance use disorders.
       No cocaine use1,293,50964,30834.0 (33.7-34.2)ReferentReferent
      low asterisk Adjusted for age, parity, mental illness, tobacco use, comorbidity, socioeconomic deprivation, place of residence, and time period.
      Additionally adjusted for other substance use disorders.
      Cocaine use disorders were associated with several cardiovascular outcomes (Table 3). Compared with no cocaine use disorder, women with cocaine use disorders had more than 3 times the risk of valve disease and inflammatory heart disease. Cocaine use disorders were associated with more than twice the risk of cardiac arrest, other pulmonary vascular disease, other cerebrovascular disease, and arterial embolism. Cocaine use disorders were associated with more than 1.5 times the risk of heart failure, myocardial infarction, conduction disorder, pulmonary embolism, and admission to a coronary care unit.
      Table 3Association of Cocaine Use Disorder with Specific Cardiovascular Outcomes
      Cocaine Use DisorderNo Cocaine Use DisorderHazard Ratio

      (95% Confidence Interval)
      Hazard ratio for cocaine use disorder vs. no disorder, adjusted for age, parity, mental illness, other substance use disorders, tobacco use, comorbidity, socioeconomic deprivation, place of residence, and time period.
      No. EventsIncidence per 10,000 Person-YearsNo. EventsIncidence per 10,000 Person-Years
      Heart
       Heart failure349.030811.61.88 (1.25-2.81)
       Myocardial infarction3810.156672.91.67 (1.16-2.40)
       Other ischemic heart disease133.415650.81.87 (1.01-3.46)
       Angina123.228431.51.33 (0.70-2.53)
       Cardiac arrest154.08910.52.93 (1.46-5.88)
       Inflammatory heart disease349.09600.54.82 (2.97-7.83)
       Conduction disorder6216.611,7546.11.57 (1.18-2.09)
       Valve disease379.827001.43.09 (2.11-4.51)
       Cardiomyopathy154.019101.01.37 (0.77-2.44)
      Lungs
       Pulmonary embolism379.846482.41.83 (1.26-2.67)
       Other pulmonary vascular disease184.812620.72.37 (1.40-4.02)
      Cerebrovascular
       Ischemic stroke184.828021.41.50 (0.87-2.60)
       Hemorrhagic stroke112.922271.11.42 (0.72-2.79)
       Other cerebrovascular disease225.821691.12.43 (1.48-4.00)
      Hypertension16244.040,66321.31.16 (0.98-1.39)
      Atherosclerosis4211.275923.91.42 (1.00-2.01)
      Aortic aneurysm or dissection<50.33660.20.79 (0.08-8.03)
      Aneurysm of other vessels82.116260.81.58 (0.70-3.58)
      Arterial embolism143.710180.52.22 (1.19-4.14)
      Cardiovascular intervention6617.710,9865.71.62 (1.24-2.13)
       Heart procedure308.064623.31.30 (0.88-1.93)
       Vessel procedure92.420551.11.32 (0.65-2.69)
       Coronary care unit admission369.647062.41.77 (1.22-2.57)
      low asterisk Hazard ratio for cocaine use disorder vs. no disorder, adjusted for age, parity, mental illness, other substance use disorders, tobacco use, comorbidity, socioeconomic deprivation, place of residence, and time period.
      Cocaine use disorders were associated with cardiovascular hospitalization at all points over time (Table 4). Women with cocaine use disorders were, however, at greatest risk of cardiovascular hospitalization at 5 to 9 years of follow-up (HR 2.15; 95% CI, 1.70-2.72). At 5 to 9 years, cocaine use disorders were associated with 3 to 9 times the risk of pulmonary embolism, other pulmonary vascular disease, and cardiac complications such as heart failure, myocardial infarction, cardiac arrest, inflammatory heart disease, and valve disease. At 10 to 14 years of follow-up, women with cocaine use disorders remained at risk of pulmonary embolism, other pulmonary vascular disease, heart failure, and inflammatory heart disease. Cocaine use disorders were associated with cerebrovascular disease at 15 years of follow-up or more.
      Table 4Association of Cocaine Use Disorder with Specific Cardiovascular Outcomes According to Follow-Up Period
      Hazard Ratio

      (95% Confidence Interval)
      Hazard ratio for cocaine use disorder vs. no disorder, adjusted for age, parity, mental illness, other substance use disorders, tobacco use, comorbidity, socioeconomic deprivation, place of residence, and time period.
      <5 Years5-9 Years10-14 Years≥15 Years
      Any cardiovascular event1.59 (1.24-2.03)2.15 (1.70-2.72)1.26 (0.95-1.68)1.38 (1.10-1.72)
      Heart
       Heart failure1.01 (0.39-2.58)4.08 (1.78-9.33)4.18 (1.98-8.80)1.15 (0.53-2.49)
       Myocardial infarction1.15 (0.32-4.11)3.46 (1.62-7.38)1.43 (0.68-3.03)1.44 (0.84-2.48)
       Other ischemic heart disease7.38 (2.48-21.9)0.66 (0.08-5.23)1.99 (0.50-7.96)0.71 (0.17-2.92)
       Angina2.73 (0.66-11.3)1.58 (0.42-5.95)0.36 (0.05-2.69)1.47 (0.54-3.99)
       Cardiac arrest1.01 (0.22-4.55)7.96 (2.37-26.8)3.36 (0.79-14.3)3.47 (0.90-13.4)
       Inflammatory heart disease4.19 (1.65-10.6)6.93 (3.25-14.8)8.03 (2.59-24.9)2.79 (0.86-9.10)
       Conduction disorder1.45 (0.80-2.63)2.30 (1.38-3.84)1.21 (0.58-2.52)1.46 (0.86-2.50)
       Valve disease3.73 (1.75-7.93)7.27 (3.69-14.3)2.28 (0.75-6.92)1.56 (0.74-3.33)
       Cardiomyopathy1.73 (0.66-4.52)0.48 (0.06-3.67)3.26 (0.99-10.7)1.13 (0.40-3.17)
      Lungs
       Pulmonary embolism0.97 (0.44-2.15)3.71 (1.84-7.48)2.61 (1.13-5.98)1.28 (0.58-2.85)
       Other pulmonary vascular disease4.81 (1.54-15.1)3.81 (1.38-10.5)4.20 (1.25-14.2)1.14 (0.44-2.90)
      Cerebrovascular
       Ischemic stroke2.65 (0.73-9.58)0.71 (0.15-3.34)1.19 (0.37-3.83)1.86 (0.84-4.11)
       Hemorrhagic stroke0.95 (0.20-4.54)1.12 (0.26-4.88)1.05 (0.25-4.41)2.56 (0.85-7.74)
       Other cerebrovascular disease2.47 (0.86-7.05)3.38 (1.26-9.06)1.41 (0.42-4.71)2.84 (1.29-6.27)
      Hypertension0.95 (0.62-1.48)1.43 (1.00-2.05)1.01 (0.68-1.48)1.25 (0.96-1.63)
      Atherosclerosis2.37 (0.93-6.05)2.48 (1.08-5.68)1.48 (0.73-2.98)0.97 (0.56-1.68)
      Aortic aneurysm or dissection---3.82 (0.28-52.5)
      Aneurysm of other vessels-1.64 (0.24-11.3)2.29 (0.57-9.21)2.03 (0.60-6.89)
      Arterial embolism2.78 (0.87-8.84)2.83 (0.89-9.04)1.09 (0.14-8.29)2.16 (0.71-6.53)
      Cardiovascular intervention1.89 (1.09-3.29)3.31 (1.98-5.52)0.83 (0.38-1.77)1.36 (0.86-2.17)
       Heart procedure1.50 (0.62-3.62)3.34 (1.65-6.79)0.88 (0.33-2.32)0.85 (0.41-1.76)
       Vessel procedure1.18 (0.27-5.11)0.70 (0.10-5.35)0.78 (0.08-7.83)2.09 (0.82-5.33)
       Coronary care unit admission2.10 (1.01-4.38)5.20 (2.61-10.4)0.62 (0.19-1.99)1.26 (0.64-2.48)
      low asterisk Hazard ratio for cocaine use disorder vs. no disorder, adjusted for age, parity, mental illness, other substance use disorders, tobacco use, comorbidity, socioeconomic deprivation, place of residence, and time period.
      Supplementary TableIncidence of Cardiovascular Hospitalization According to Women's Characteristics at Start of Follow-Up
      No. WomenNo. Cardiovascular HospitalizationsPerson-YearsIncidence per 10,000 Person-Years (95% Confidence Interval)
      Cocaine use disorder
       Yes295434535,36097.6 (87.8-108.4)
       No1,293,50964,30818,922,81134.0 (33.7-34.2)
      Age, years
       <25153,28065102,354,35927.7 (27.0-28.3)
       25-34868,93342,29313,060,57532.4 (32.1-32.7)
       ≥35274,25015,8503,543,23744.7 (44.0-45.4)
      Parity
       1555,44333,6268,988,44037.4 (37.0-37.8)
       2533,31222,6097,512,77530.1 (29.7-30.5)
       ≥3207,70884182,456,95634.3 (33.5-35.0)
      Mental illness
      Schizophrenia, depression, bipolar, anxiety, stress, personality disorders, and suicide attempt.
      46,9332539419,35060.5 (58.2-62.9)
      Other substance use disorder
      Alcohol, opioids, cannabis, stimulants, hallucinogens, sedatives, hypnotics, and volatile solvents.
      15,5991094152,75271.6 (67.5-76.0)
      Tobacco use35,9312208403,91154.7 (52.4-57.0)
      Comorbidity
      Preexisting or gestational diabetes, obesity, and dyslipidemia.
      145,83210,0401,587,60163.2 (62.0-64.5)
      Socioeconomic deprivation248,02114,0933,473,57440.6 (39.9-41.2)
      Rural residence236,28613,7503,527,00039.0 (38.3-39.6)
      Time period
       1989-1998430,15845,49210,834,87242.0 (41.6-42.4)
       1999-2008339,92514,3415,301,03727.1 (26.6-27.5)
       2009-2019526,38048202,822,26217.1 (16.6-17.6)
      Total1,296,46364,65318,958,17134.1 (33.8-34.4)
      low asterisk Schizophrenia, depression, bipolar, anxiety, stress, personality disorders, and suicide attempt.
      Alcohol, opioids, cannabis, stimulants, hallucinogens, sedatives, hypnotics, and volatile solvents.
      Preexisting or gestational diabetes, obesity, and dyslipidemia.
      In sensitivity analyses, the association with cardiovascular hospitalization strengthened when cocaine use disorders were measured as a time-varying exposure (HR 2.17; 95% CI, 1.94-2.42). The association between cocaine use disorders and cardiovascular hospitalization strengthened in models not adjusted for other substance use disorders (HR 2.01; 95% CI, 1.79-2.24) and in models restricted to primiparous women aged 35 years or more (HR 1.70; 95% CI, 1.12-2.59).

      Discussion

      Cocaine use is an understudied public health problem that is prevalent in North America, but has considerable potential to contribute to cardiovascular morbidity. In this cohort of 1.3 million women of reproductive age followed for up to 31 years, women with cocaine use disorders had an elevated risk of a range of adverse cardiovascular outcomes, including inflammatory heart disease, cardiac arrest, valve disease, and arterial embolism. Women with cocaine use disorders were at greatest risk of cardiovascular events 5 to 10 years after the start of follow-up. The data suggest that cocaine use may increase the risk of cardiovascular disease in the medium term.
      Cocaine use increases heart rate and blood pressure,
      • Braun BL
      • Murray DM
      • Sidney S
      Lifetime cocaine use and cardiovascular characteristics among young adults: the CARDIA study.
      and is known for its acute cardiovascular complications after short-term use, including heart failure, myocardial infarction, stroke, and sudden death.
      • Schwartz BG
      • Rezkalla S
      • Kloner RA
      Cardiovascular effects of cocaine.
      ,
      • Morentin B
      • Ballesteros J
      • Callado LF
      • Meana JJ
      Recent cocaine use is a significant risk factor for sudden cardiovascular death in 15-49-year-old subjects: a forensic case-control study.
      However, data on the medium- or long-term risk of cardiovascular disease remain limited or inconclusive.
      • Braun BL
      • Murray DM
      • Sidney S
      Lifetime cocaine use and cardiovascular characteristics among young adults: the CARDIA study.
      ,
      • Kim ST
      • Park T
      Acute and chronic effects of cocaine on cardiovascular health.
      • Thylstrup B
      • Clausen T
      • Hesse M
      Cardiovascular disease among people with drug use disorders.
      • DeFilippis EM
      • Singh A
      • Divakaran S
      • et al.
      Cocaine and marijuana use among young adults with myocardial infarction.
      • Qureshi AI
      • Chaudhry SA
      • Suri MF
      Cocaine use and the likelihood of cardiovascular and all-cause mortality: data from the Third National Health and Nutrition Examination Survey Mortality Follow-up Study.
      A retrospective cohort study of 2097 young adults with a history of myocardial infarction reported that cocaine use was associated with 2.3 times the risk of cardiovascular death and 1.9 times the risk of all-cause mortality during a median of 11 years of follow-up.
      • DeFilippis EM
      • Singh A
      • Divakaran S
      • et al.
      Cocaine and marijuana use among young adults with myocardial infarction.
      In contrast, regular cocaine use was associated with all-cause but not cardiovascular mortality in a study of 9013 adults aged <45 years with a mean of 15 years of follow-up.
      • Qureshi AI
      • Chaudhry SA
      • Suri MF
      Cocaine use and the likelihood of cardiovascular and all-cause mortality: data from the Third National Health and Nutrition Examination Survey Mortality Follow-up Study.
      Another study of 16,820 individuals found that cocaine use disorders were not associated with cardiovascular disease over a mean of 7.5 years; however, the comparison group included patients with other substance use disorders.
      • Thylstrup B
      • Clausen T
      • Hesse M
      Cardiovascular disease among people with drug use disorders.
      In our study with larger sample and longer follow-up, cocaine use disorders were associated with approximately 50% greater risk of cardiovascular disease compared with no cocaine use disorder.
      Sex-specific associations are less understood, particularly for women. A growing number of women use cocaine over time.
      • Kariisa M
      • Scholl L
      • Wilson N
      • Seth P
      • Hoots B
      Drug overdose deaths involving cocaine and psychostimulants with abuse potential - United States, 2003-2017.
      A sex-stratified analysis of 2121 young women found that lifetime cocaine use was associated with a nonsignificant twofold greater odds of hypertension up to 5 years later.
      • Braun BL
      • Murray DM
      • Sidney S
      Lifetime cocaine use and cardiovascular characteristics among young adults: the CARDIA study.
      Women who use cocaine during pregnancy are more likely to report poor physical and mental health 10 years after delivery.
      • Minnes S
      • Min MO
      • Singer LT
      • Edguer M
      • Wu M
      • Thi P
      Cocaine use during pregnancy and health outcome after 10 years.
      Prenatal cocaine use is associated with 1.8 times greater odds of acute myocardial infarction and cardiac arrest during pregnancy and delivery.
      • Salihu HM
      • Salemi JL
      • Aggarwal A
      • et al.
      Opioid drug use and acute cardiac events among pregnant women in the United States.
      These scattered analyses are the extent of what is known about the adverse effects of cocaine in women. Our study provides novel evidence that women with cocaine use disorders prior to or during pregnancy are at greater risk of cardiovascular events several years later.
      Cocaine blocks presynaptic reuptake of dopamine and norepinephrine, decreasing blood flow and increasing demand for oxygen.
      • Talarico GP
      • Crosta ML
      • Giannico MB
      • Summaria F
      • Calò L
      • Patrizi R
      Cocaine and coronary artery diseases: a systematic review of the literature.
      ,
      • Kim ST
      • Park T
      Acute and chronic effects of cocaine on cardiovascular health.
      These changes may be followed by acute increases in blood pressure and heart rate contributing to early coronary events, including myocardial infarction.
      • Talarico GP
      • Crosta ML
      • Giannico MB
      • Summaria F
      • Calò L
      • Patrizi R
      Cocaine and coronary artery diseases: a systematic review of the literature.
      ,
      • Kim ST
      • Park T
      Acute and chronic effects of cocaine on cardiovascular health.
      Regular cocaine use is associated with 1.3 times greater odds of acute arrhythmias and 3 times greater odds of myocardial infarction,
      • Winhusen T
      • Theobald J
      • Kaelber DC
      • Lewis D
      The association between regular cocaine use, with and without tobacco co-use, and adverse cardiovascular and respiratory outcomes.
      with the greatest risk of myocardial infarction in the first hour after use.
      • Mittleman MA
      • Mintzer D
      • Maclure M
      • Tofler GH
      • Sherwood JB
      • Muller JE
      Triggering of myocardial infarction by cocaine.
      However, we demonstrated that the threefold greater risk of myocardial infarction may extend up to 5 to 9 years later.
      Short-term use of cocaine is associated with acute cerebrovascular complications, including hemorrhagic and ischemic stroke,
      • Winhusen T
      • Theobald J
      • Kaelber DC
      • Lewis D
      The association between regular cocaine use, with and without tobacco co-use, and adverse cardiovascular and respiratory outcomes.
      with the greatest risk occurring within 24 hours of use.
      • Cheng YC
      • Ryan KA
      • Qadwai SA
      • et al.
      Cocaine use and risk of ischemic stroke in young adults.
      However, our findings suggest that cocaine use may also be associated with the risk of cerebrovascular disease and cerebrovascular vessel interventions more than 15 years later.
      Cocaine may, moreover, be associated with arterial embolism and pulmonary disease up to 15 years after use. While little is known of the association between cocaine and these cardiovascular outcomes, chronic use of cocaine is a suspected cause of endothelial cell dysfunction, bradycardia, and aortic stiffness, even in the absence of an acute cardiovascular event.
      • Chen DH
      • Kolossváry M
      • Chen S
      • Lai H
      • Yeh HC
      • Lai S
      Long-term cocaine use is associated with increased coronary plaque burden – a pilot study.
      ,
      • Kim ST
      • Park T
      Acute and chronic effects of cocaine on cardiovascular health.
      Lack of recovery of normal cardiovascular physiology after cocaine use could explain the associations we observed, although more research is needed to identify the pathways involved.
      In our population, women who used cocaine alone or with other substances had similar risks of cardiovascular hospitalization later in life. In contrast, other studies report greater risks of cardiovascular disease when cocaine is combined with other substances.
      • Auger N
      • Paradis G
      • Low N
      • Ayoub A
      • He S
      • Potter BJ
      Cannabis use disorder and the future risk of cardiovascular disease in parous women: a longitudinal cohort study.
      ,
      • Salihu HM
      • Salemi JL
      • Aggarwal A
      • et al.
      Opioid drug use and acute cardiac events among pregnant women in the United States.
      ,
      • Phillips K
      • Luk A
      • Soor G
      • et al.
      Cocaine use is associated with a number of life-threatening cardiovascular complications that require careful treatment.
      Alcohol increases plasma concentration of cocaine compared with cocaine taken alone, and concurrent use of these 2 substances is associated with a higher risk of sudden cardiac death.
      • Lange RA
      • Hillis LD
      Sudden death in cocaine abusers.
      Although in our study both isolated and combined cocaine use disorders were associated with cardiovascular hospitalization, we cannot rule out the possibility that polysubstance use exacerbates the risk of adverse cardiovascular events.
      We analyzed a large population-based cohort of parous women with 3 decades of follow-up, but the study is not without limitations. We could not account for cocaine use disorders that did not lead to hospitalization prior to pregnancy and cannot confirm that women were screened for drug use. The number of women with cocaine use disorders may therefore be underestimated. The rate of cocaine use disorders in our study (0.2%) is comparable with the United States (0.3%),
      • Salihu HM
      • Salemi JL
      • Aggarwal A
      • et al.
      Opioid drug use and acute cardiac events among pregnant women in the United States.
      but findings may not generalize to the larger number of women who use cocaine only occasionally. We could not determine whether cocaine use was self-reported or detected through toxicology screen. We were unable to determine the frequency, quantity, and duration of cocaine use; studies with access to such information are needed to develop and improve interventions for long-term health. We suspect that the risk of cardiovascular disease may be greater among chronic cocaine users. Results for rare cardiovascular events should be interpreted with caution. In addition, results may be affected by residual confounding due to incomplete data on potential confounders, such as smoking, body mass index, nutritional factors, and ethnicity. We lacked data on number of postnatal visits, although all women have free universal health care in Quebec. More studies are needed to determine the generalizability of the findings to nulliparous women.

      Conclusions

      Cocaine use is common among young women, yet its long-term cardiovascular effects are poorly understood. This large cohort study suggests that women with cocaine use disorders early in life are at risk of cardiovascular disease several decades later. The findings highlight the need to better document the implications of cocaine for health over the life course. Interventions and strategies targeting young women at high risk of cocaine use, including women who misuse other substances or are in precarious situations, may be merited. Women may stop using cocaine to protect their fetus, thus, drug cessation interventions may be more effective during pregnancy and may also help prevent postpartum relapse. Pregnancy may be an optimal time to screen for cocaine use and educate or counsel women. Clinicians and public health practitioners should be aware of the long-term risk of cardiovascular disease in women with cocaine use disorders to ensure appropriate surveillance and clinical management.

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